The present invention relates to new photoinitiators capable of acting as photocrosslinkers providing a combination of photoinitiating and crosslinking processes.
The UV curing of resin formulations is widely used in industry as the setting process for coatings, adhesives, and more recently paints. Such formulations may comprise a combination of vinyl, usually acrylate, monomers and crosslinkers, together with a photoinitiator. Other possible constituents of the formulations include crosslinkers and vehicles. In general an advantage of photocurable formulations is that the monomers act as their own vehicle, and the use of solvent is obviated, which has environmental advantages.
Advances in the technology of photocuring, improvements such as, those in UV lamps, cationic initiators for epoxide-based formulations, water borne coatings, and many novel monomers has enabled this production process to penetrate a number of important manufacturing sectors. Photopolymerization is now used in photoresists for printed circuits and microelectronics, for photolithography, magnetic recording media, glass-fiber laminates, and for medical devices, especially for dental and ophthalmic applications.
For the medical applications of photopolymerisation it is usual to employ visible light, rather than UV, to effect the cure of the resin formulation. The use of visible, usually blue, light avoids exposing patient and dentist or surgeon to harmful irradiation. Increasingly the merit of this approach is being recognized for industrial practice, where operatives also need protection from prolonged exposure to harmful UV.
European Patent 0800 657 describes a photoinitiator linked to a macromer structure which together with a copolymerizable monomer and a crosslinker is capable forming a polymerization product, such as an ophthalmic lens that retains photoinitiator radical in the resulting network. This is advantageous in medical applications wherein such potentially harmful radicals must be carefully controlled. However, this system would not be applicable for producing a polymerized product directly in the capsular bag in the eye since it is not directed to photoinitiators activated by light in the visible range, U.S. Pat. No. 4,536,265 discloses siloxane polyphotoinitiators to be used with a curable silicone resin. This system is UV curable and consequently it will not be applicable for photocuring in the living eye.
It is a characteristic of almost all, if not all, of the formulations used for aforementioned types of application that they are crosslinked. Crosslinking of the polymeric bases which constitute the coatings or artifacts of the aforementioned industrial products confers important advantages upon them. Crosslinked polymers have greater environmental (e.g. temperature and moisture) resistance, solvent resistance and dimensional and mechanical stability, than equivalent linear polymers. This is especially so for where the equivalent linear polymer are produced by photopolymerisation they have an atactic, non-crystalline, structure.
Crosslinking is introduced into photopolymerized products by including in the formulation for the resin, coating or gelling system an acrylate, or similar, crosslinker, which is characterized by having two or more crosslinkable acrylate or vinyl functions. In some formulations this crosslinking species is a polymer of low molecular weight. The crosslinker copolymerizes with the monomers of the formulation to produce a network structure.
It is the object of the present invention provide compounds which act as photocrosslinkers for vinyl, acrylate and methacrylate monomers and acrylated silicone compositions, especially in solution.
It is also an important object of the present invention to provide photocrosslinkers with capability to act in aqueous solutions, especially on water soluble macromolecular particles having functional groups for crosslinking.
It is another object of the present invention to provide photocrosslinkers with enhanced photoactivity (100% conversion of monomer to polymer in aqueous solution) which reduces photoinitiator residues to a minimum, especially, vinyl modification of photoinitiator component and thereby reducing compositional drift, Draize and other environmental hazards.
The invention as presented below will explain bow the mentioned objects are met while discussing further obvious advantages.
The present invention pertains to macromolecular hydrophilic photocrosslinkers having a general formula (A)n(B)m(C)p, wherein
(i) A, B and C are units of substituted ethylene or siloxane groups in the macromolecular structure;
(ii) A, B and C are randomly distributed and the unit C carries a photoactive group;
(iii) n=0-98 mole %, m=0-98 mole %, n+m=50-98 mole % and p=0.5-50 mole %.
When the photoactive groups of units C are exposed to light of determined wavelengths above 305 nm, radicals arc generated which are retained on the macromolecular photocrosslinkers and will react to form a crosslinked network structure. Preferably the final structure is solid article.
The photocrosslinker further preferably further comprises functional groups for crosslinking. Such groups are conventionally vinylic, acrylic or methacrylic groups and their nature and introduction on polymeric backbone are well known to persons skilled in the art and will be referred to as xe2x80x9cfunctional groups for crosslinkingxe2x80x9d.
According to one aspect of the invention a fluid composition of the photocrosslinker in a suitable amount can be directly crosslinked into the final solid product upon sufficient irradiation. In another aspect the composition for crosslinking into a solid article comprises suitable amounts of the photocrosslinker and a polymer carrying functional groups for crosslinking. The photocrosslinker in such a system will thereby replace the conventional combination of crosslinker and photoinitiator. Applicable polymers with suitable functional can readily be provided with the skilled person for the purpose of crosslinking desired articles. For example it would be conceivable to employ polymers having a sufficiently high refractive index to be acceptable as intraocular lenses. Suitable polymers can be, for example, be found in International Patent Application PCT/EP99/07718. In a still another aspect of the present invention, the photocrosslinkers can be employed in a composition, preferably an aqueous composition further comprising at least one copolymerizable vinylic, acrylic or methacrylic monomer. Such monomers and combinations thereof are well known in the art and will not be described herein in further detail. It is, however, to be understood that the photocrosslinker will replace conventional crosslinking agents and their combination with photoinitiators in such systems.
It is highly preferred that the photoactive groups of the photocrosslinkers comprise a phosphine oxide, in order to generate the necessary radicals for crosslinking from the exposure of visible light. More preferably, the photoactive group is an acyl- or aroyl phosphine oxide.
According to a preferred aspect, the photoactive group is linked to the ethylene groups of units C of the photocrosslinkers by a linking group comprising a phenylene group. Optionally, such a phenylene group is substituted in order to obtain more stability.
According to one embodiment of the invention, the photocrosslinkers comprises substituted ethylene units A, B, C of a macromolecular photocrosslinker in according to:
A=xe2x80x94CH2xe2x80x94C(R1R2)xe2x80x94, B=xe2x80x94CH2xe2x80x94C(R1R3)xe2x80x94, C=xe2x80x94CH2xe2x80x94C(R1R4)xe2x80x94, wherein
R1 is hydrogen or methyl;
R2 is xe2x80x94CON(Me)2, xe2x80x94CO2CH2CH2OH, xe2x80x94OCOCH3, xe2x80x94OCOCH2CH2Ph, xe2x80x94OH or a lactam group;
R3 is xe2x80x94CON(Me)2, xe2x80x94CO2CH2CH2OH, xe2x80x94OCOCH3, xe2x80x94OCOCH2CH2Ph, xe2x80x94OH or a lactam group when B is xe2x80x94CH2xe2x80x94C(R1R3)xe2x80x94 with the proviso that R2 and R3 are not the same; and
R4 is xe2x80x94R5C(O)P(O) R6R7 or xe2x80x94R5P(O)R6OC(O)R7, wherein R5, R6 and R7 are selected among same or different aryl groups comprising phenyl, methylphenyl, dimethylphenyl, trimethylphenyl, methoxyphenyl, dimethoxyphenyl, trimethoxyphenyl, methylolphenyl, dimethylolphenyl, trimethylolphenyl or styryl radicals, or
In the general formula above, xe2x80x94OH denotes a hydroxyl group, Me a methyl group and Ph is a phenyl group. The lactam group typically is a heterocyclic ring structure of 4 to 7 atoms of which at least one is nitrogen. A suitable such lactam group provides a N-vinyl-pyrrolidone structure as one of units A or B on said ethylenic backbone. It is also to be understood that besides the mentioned substituents functional groups for crosslinking can be added to the marcromolecule in accordance with conventional methods.
In one advantageous aspect of this embodiment, the photocrosslinkers, R2 and R3 according to above are selected so as to form a water-soluble molecule.
Suitable units A and B in the general formula (A)n(B)m(C)p are selected among, but not limited to, N-vinylpyrrolidone (NVP), 2-hydroxyethylmethacrylate, N-N-dimethylacrylamide and vinyl acetate. The vinyl acetate referred to preferably will be hydrolyzed conventionally to vinyl alcohol. It is also referred to Table 1 below in the exemplifying part of the description for a number of specific photocrosslinkers based on such units (or co-monomers) and 4-vinylbenzoyl-diphenylphosphine oxide (VBPO) as a photoinitiating group. Accordingly, VBPO units constitute units C in said general formula above. Some especially suitable water soluble, blue light activated photocrosslinkers according to the present invention comprise NVP together with vinyl acetate units, N,N-dimethylacrylamide units alone or together with 2-hydroxyethylethacrylate units, all combined with VBPO units. These photocrosslinkers demonstrate high conversion rate (monomer to polymer) and suitably high stability in aqueous solution. This type of photocrosslinkers can be prepared by conventional radical polymerization.
According to another embodiment, the photocrosslinkers described above with general formula can comprise units A, B and C which are siloxane monomer units having a formula
xe2x80x94RaRbSiOxe2x80x94, wherein Ra and Rb in units A and B are selected among lower substituted or unsubstituted alkyl groups, aryl groups and arylalkyl groups. Preferably, at least on of Ra and Rb is an aryl or arylalkylgroup. More preferably Ra and Rb is substituted with one or more fluorine atoms. Alkyl groups in this context means a C1 to C10 alkyl group which is straight or branched.
According to a preferred aspect of this embodiment the siloxane units comprising substituents in accordance with:
A is xe2x80x94Si(R1R2)xe2x80x94Oxe2x80x94, B is xe2x80x94Si(R1R3)xe2x80x94Oxe2x80x94 and C is xe2x80x94Si(R1R4)xe2x80x94Oxe2x80x94, wherein
R1 is C1 to C6 alkyl; R2 is C1 to C6 alkyl or phenyl; R3 is R1, R2or C1 to C6 fluroalkyl;
R4 is xe2x80x94R5R6C(O)P(O) R7R8 or xe2x80x94R5 R6P(O)R7OC(O)R8, wherein R5 is a spacing group; R6, R7 and R8 are selected among, same or different aryl groups comprising phenyl, methylphenyl, dimethylphenyl, trimethylphenyl, methoxyphenyl, dimethoxyphenyl, trimethoxyphenyl, methylolphenyl, dimethylolphenyl, trimethylolpheny or styryl radicals.
The aliphatic spacing group R5 is preferably comprises between one and ten atoms and suitably
The spacing group is (xe2x80x94CH2)n, wherein n is between 1 and 10.
According to an aspect of the invention particularly suitable for the production of ophthalmic lenses, the photocrosslinkers has radicals connected to the polysiloxane backbone such that R1is methyl; R2 is methyl or phenyl; and R3 is R1, R2 or xe2x80x94CH2CH2CF3. Such polysiloxane photocrosslinkers may have functional acrylic groups in its terminal ends. Polysiloxanes of this type and their applicability and advantages, especially for injectable intraocular leases, are disclosed in the International Patent Application PCT/EP99/07781 which document herewith is incorporated as a reference.
The present invention further involves a method of forming a macromolecular crosslinked network from a fluid composition comprising photocrosslinkers according to any of the mentioned embodiments by irradiating said composition with light exceeding a wavelength of about 305 nm for a time sufficient to form a solid article. The composition can comprise said
photocrosslinkers at least one copolymerizable vinylic, acrylic or methacrylic monomer, or the composition can comprise a polymer provided with functional vinylic, acrylic or methacrylic groups. It would be obvious to the skilled person to combine any such monomers and polymers together with the inventive photocrosslinkers and also, if found advantageous, combining the composition with a conventional crosslinker suitable for the specifically selected composition. It is further to be understood that the constituents of such a composition shall be selected so as be sufficiently compatible to each other and the selected fluid environment, for example depending on if photocrosslinkers having ethylene or polysiloxane backbone are selected.
In an especially advantageous application of the method, a medical device or medical implant such an ophthalmic lens is produced by means of a conventional molding method wherein the photocrosslinking into a network is a conventional curing process. The inventive method is particularly suitable for producing an intraocular lens by means of injection and subsequent photocrosslinking direct in the capsular bag of eye, from which the natural lens has been surgically removed.
It is also a part of the present invention provide an ophthalmically acceptable composition comprising the new photocrosslinkers. Such a composition will typically have a refractive index greater than about 1.39 and a viscosity such that said composition can be injected through standard cannula having a needle of 15 Gauge, or finer. Such a composition can further comprise of any suitable constituents as outlined above that can be a part of the network provided by the subsequent photocrosslinking.
The photocrosslinkers according to the present invention provide for a combination of photoinitiating and crosslinking processes. It is an important feature of the present invention to effect this combination of function by attaching photoactive groups to a polymeric or macromolecular structure. The photoactive groups, when exposed to light of the appropriate wavelength, will undergo photoinduced scission and generating radicals, which are retained on the polymeric or macromolecular structure. These retained radicals then initiate, terminate, or, in some other way participate in the gel forming process that is the objective of the radiation cure of the photomaterial. The use of the inventive photocrosslinkers confers distinct advantages, both chemical and environmental, as compared with the combination of a separate photoinitiator and crosslinker. In a chemical context the use of a photocrosslinker gives opportunities to produce networks that are more homogeneous than those produced by photocuring conventional photocurable systems. The latter systems, involving as they do, combinations of monomers, have structures dependent on the reactivity ratios of the monomers and crosslinkers. Often, for example, in a coating being manufactured at high rates of production, a crosslinker is selected because of its high reactivity. Disparities in the reactivates of the components of a formulation gives rise to compositional drift, the change of the average unit composition during the course of a polymerization, and this in relation to a reactive crosslinker implies that sections of a network forming later, in the curing process, have a lower crosslink density than sections formed earlier. Improving the homogeneity of crosslinked networks is a subject receiving greater attention as the technical demands imposed on industrial products increases. Homogenous networks have, for example, higher fracture toughness and better optical properties heterogeneous networks. The shrinkage occurring during their formation is more uniform allowing for more precision in castings. The benefits of using a photocrosslinker as a network former, as compared with a combination of photoinitiator and crosslinker, arise because the radical species they produce act as crosslinkers via the polymer chain to which they are attached. Further such radicals are generated throughout the setting phase, their concentration being controlled by the photoinitiating species"" quantum efficiency and the intensity of the light, which may be modulated during the setting, in addition to its concentration. This distinction results in the formation of networks having a more controlled and homogeneous structure.
Retaining photoinitiator residues in the network of a medical product, such as a contact lens or a dental filling has desirable physiological implications. Further photocrosslinkers because of their polymeric, or macromolecular, nature are more acceptable, environmentally, than many conventional crosslinkers which are known to cause skin and lung irritation.
Within the context of the present invention, it is possible to substitute a photocrosslinker, either completely, or partially, for a combination of a conventional photoinitiator and a conventional crosslinker. Alternatively, the inventive photocrosslinkers can be used in combination with a conventional photoinitiator or a conventional crosslinker, as will be understood by practitioners skilled in formulating systems for crosslinking.
Persons skilled in this art will also appreciate that the inventive photocrosslinkers as described herein for photoactive systems responsive to visible light may be applied equally to systems responsive to UV light, so the present invention is of very general applicability.